While T cells are going through selection processes to induce tolerance to self in the thymus, it is clearly not perfect. T cells sometimes do not encounter tissue specific antigens until they reach peripheral organs and autoimmune diseases develop if T cells become activated by tissue specific antigens in the periphery. It is important therefore to determine how the immune system induces and maintains tolerance to such antigens, for immune responses to these antigens lead to devastating autoimmune syndromes such as insulin dependent diabetes. The overall goal of this project is to study the biological effects of T cells in the periphery by manipulating the timing and the duration of tissue specific antigen presentation during animal's development. To achieve this goal, the investigator has already generated a novel transgenic mouse model in which MHC class II expression in the pancreas is controlled by means of a transcriptional "on/off" switch by employing the antibiotic, tetracycline. This system will allow him to manipulate the timing of MHC class II expression that coincides with the presentation of islet specific autoantigens to T cells. The investigator will then determine whether the degree of autoreactive T cell tolerance is altered by the different timing of tissue specific antigen presentation. Specifically, he will determine: (1) the minimum time requirement of antigen presentation to tolerize T cells in the periphery; (2) whether the status of T cell tolerance can be reversed depending on different environment in the pancreas; (3) how long the tissue specific antigen have to be presented to T cells to induce tolerance in the periphery; and (4) whether MHC class II expressing pancreatic beta cells can induce immune response in the absence of B cells. The investigator will then apply the same strategy to NOD mice to investigate whether the presentation of islet specific autoantigens to T cells during development can induce T cell tolerance resulting in prevention of the onset of diabetes. The results obtained are likely to be of relevance to how autoimmune responses are regulated in general.